Immunoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type 1 diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohns disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, and Graves ophthalmopathy. Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.
Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Antiinflammatory agents such as NSAID's and corticosteroids act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succoumb from infection as they are from their autoimmune disease.
The cyclosporins are a family of immunospressive compounds isolated from fermentation broths of various fungal species including Tolvoocladium inflatum and Cylindrocaroon lucidum.
The generic structure of the class of cyclosporins has been established as a cyclic peptide of formula (I) which contains 11 amino acids. ##STR1## For example, cyclosporin A of formula (II) contains several N-methylated amino acids and one novel amino acid "MeBMT" designated as the 1- "C-9 amino acid". This novel amino acid is located in position 1 and has been found to be important for the biological activity of cyclosporin. We have found that replacing the double bond of the "C-9 amino acid" (MeBMT) with a hetero atom such as S and O decreases the toxicity of the parent cyclosporin. Substantial activity in the various assays in which cyclosporin A expresses immunosuppressive activity is also exhibited. ##STR2##
Generally a cyclosporin such as cyclosporin A is not cytotoxic nor myelotoxic. It does not inhibit migration of monocytes nor does it inhibit granulocytes and macrophage action. Its action is specific and leaves most established immune responses intact. However, it is nephrotoxic and is known to cause the following undesirable side effects:
(1) abnormal liver function; PA0 (2) hirsutism; PA0 (3) gum hypertrophy; PA0 (4) tremor; PA0 (5) neurotoxicity; PA0 (6) hyperaesthesia; and PA0 (7) gastrointestinal discomfort.
Accordingly, an object of the present invention is to provide new cyclosporin analogs which will (1) restore the balance of the help-and-suppression mechanism of the immune system by acting at an earlier point than the anti-inflammatory agents and (2) induce specific long-term transplantation tolerance through a suppressor cell circuit without increasing the body's susceptibility to infection.
Another object of the present invention is to provide pharmaceutical compositions for administering to a patient in need of the treatment one or more of the active immunosuppressive agents of the present invention.
Still a further object of this invention is to provide a method of controlling graft rejection, autoimmune and chronic inflammatory diseases by administering a sufficient amount of one or more of the novel immunosuppressive agents in a mammalian species in need of such treatment.
Finally, it is the object of this invention to provide processes for the preparation of the active compounds of the present invention.